1. Field of the Invention
This invention relates to compositions and methods, including liposomal vinca alkaloids, for the treatment of neoplasias.
2. Description of the Related Art
Despite years of research into the development of new methods of treatment, many types of cancer, including, e.g., lung cancer and cancers of the lymphatic system, or lymphomas, remain quite common. Lung cancer remains the most common cancer in western countries, and approximately 80% of lung carcinomas are of the non-small cell subtype (NSCLC). Similarly, more than 60,000 people in the United States are diagnosed with lymphoma each year, including more than 55,000 cases of non-Hodgkin's Lymphoma (NHL), and these numbers are constantly increasing. The prognosis for those affected by these diseases is often poor, as the survival rates associated with many cancers, including NSCLC and lymphoma remaining low. Clearly, new methods for treating these diseases are needed.
While traditional treatments for cancers typically depend on the type and stage of the cancer as well as the medical history of the patient, treatment for many cancers includes chemotherapy. Such chemotherapy will often entail the administration of a “cocktail” of compounds, e.g., the formulation CHOP, which includes cyclophosphamide, doxorubicin, vincristine, and prednisone. In addition, chemotherapy may be combined with other forms of cancer therapy, such as radiation therapy.
Alkaloids isolated from the periwinkle plant (Vinca rosea) and derivatives thereof, collectively referred to as “vinca alkaloids,” have proven effective for first line treatments of many types of lymphomas, leukemia, and other cancers. Vincristine and vinblastine consist of a catharanthine moiety linked to vindoline, and the structures differ by a single substitution in the vindoline group. Vindesine, a desacetyl carboxyamid derivative of vinblastine, was synthesized later. Subsequently, novel synthetic approaches were used to generate compounds that differed from the natural compounds by the presence of an eight rather than a nine-member catharanthine ring, including vinorelbine tartrate (vinorelbine).
The vinca alkaloids are highly cytotoxic drugs that disrupt microtubules, inhibit cell division and induce apoptosis. Without wishing to be bound to a particular theory, it is believed that the vinca alkaloids exert their cytotoxic effects by binding to tubulin, the protein subunit of microtubules. The formation of vinca alkaloid-tubulin complexes interferes with tubulin polymerization, inhibits microtubule assembly and disrupts the mitotic spindle during cell division, resulting in cellular arrest at metaphase. Vinca alkaloids, including vinorelbine, may also exert cytotoxic effects by interfering with (1) nucleic acid and lipid biosynthesis, (2) cellular respiration, (3) calmodulin-dependent Ca2+-transport ATPase activity, and (4) amino acid, cyclic AMP and glutathione metabolism.
Vincristine, vinblastine and vinorelbine are the best-known members of this drug family and are widely used clinically. Despite having similar structures and mechanisms of action, the vinca alkaloids differ in their antitumor activity and toxicities. For example, vincristine is used mostly to treat hematological cancers, is rarely used as a single agent, and neurotoxicity is dose limiting. Vincristine is included in the common chemotherapeutic formulation CHOP. Vincristine, which depolymerizes microtubules and thereby inhibits cell proliferation, is administered in its free form in CHOP. In contrast, vinorelbine is approved for use as a single agent to treat breast and non-small cell lung cancers, and myelosuppression is dose limiting.
Lipid-encapsulated drug formulations may provide advantages over traditional drug-delivery methods. For example, some lipid-based formulations provide longer half-lives in vivo, superior tissue targeting, and decreased toxicity. In efforts to develop more effective cancer treatment, many anticancer or antineoplastic drugs have been encapsulated in liposomes. These include alkylating agents, nitrosoureas, cisplatin, antimetabolites, and anthracyclines. Studies with liposomes containing anthracycline antibiotics have clearly shown reduction of cardiotoxicity and dermal toxicity and prolonged survival of tumor bearing animals compared to controls receiving free drug.
Liposomal anticancer drugs modify drug pharmacokinetics as compared to their free drug counterpart. For a liposomal drug formulation, drug pharmacokinetics are largely determined by the rate at which the carrier is cleared from the blood and the rate at which the drug is released from the carrier. Considerable efforts have been made to identify liposomal carrier compositions that show slow clearance from the blood and long-circulating carriers have been described in numerous scientific publications and patents. Efforts have also been made to control drug leakage rates from liposomal carriers, using for example, transmembrane potential to control release.
Although numerous methods have been described for the formulation of lipid-based drug delivery vehicles (see, e.g., U.S. Pat. No. 5,741,516), previous studies have not demonstrated that liposome-encapsulated vinca alkaloid formulations offer advantages over previous treatments or have efficacy in the in vivo treatment of cancer in a patient. Liposome-encapsulated vincristine has been reported, but successful clinical applications of this technology have never been achieved (see, e.g., U.S. Pat. No. 5,741,516, or U.S. Pat. No. 5,714,163). Indeed, major theoretical and practical uncertainties remain, including uncertainties regarding biodistribution, toxicity, and efficacy. Accordingly, there is a need in the art for liposomal formulations of vinca alkaloids for the treatment of cancer.